In a recently posted warning letter, FDA cited a drug manufacturer for failing to validate the manufacturing process for tablets. FDA collected three samples during the inspection and laboratory results identified that all three were sub-potent for the active ingredient and one of the samples failed for content uniformity.
One of the key reasons for validation is to understand the sources of variability in the manufacturing process and once known to control the variability in order to consistently produce products that meet specification.
Fundamentally this is addressed in the 3 stages of process validation:
As identified in the process validation guidance:
A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of the manufacturing process that results in products with the desired quality attributes. Manufacturers should:
Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product.
Focusing exclusively on qualification efforts without also understanding the manufacturing process and associated variations may not lead to adequate assurance of quality. [italics added] After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.
One way to examine the manufacturing process is through the concept of Dominance as described in Juran’s Quality Handbook pages 4.14, 22.33, and control tools as identified in table 22.9. For a brief summary see Application of Dominance to Validation.
The warning letter tasked the manufacturer with providing the following information in response to the warning letter:
Common questions to consider:
Have the sources of variation been identified in the manufacturing process?
Is the process control strategy adequate?
Has post validation monitoring verified the process has remained in control?
Is there process drift? Have new sources of variation been introduced into the manufacturing process?